La nanomédecine est un secteur d’activité en plein essor depuis le développement des liposomes, nanovecteurs permettant d’encapsuler des molécules hydrosolubles ou amphiphiles pour la délivrance de médicament. Les nouveaux agents thérapeutiques synthétisés étant de plus en plus lipophiles, le développement de nouveaux vecteurs nanoparticulaires permettant leur transport constitue aujourd’hui un enjeu majeur. Les lipidots, nanoparticules lipidiques solides biocompatibles de 50 nm de diamètre, composées d’un mélange d’huile, de cire et de lécithine stabilisées par une couronne de surfactants pegylés, permettent de transporter des composés hautement hydrophobes en leur cœur. Des agents nucléaires pour la tomographie à émission monophotonique et des agents de fluorescence ont pu y être encapsulés pour l’évaluation de la biodistribution de ces nanoparticules chez la souris saine ainsi que dans différents modèles tumoraux. Un peptide de ciblage, le cRGD a également été greffé à la surface des lipidots afin d’adresser préférentiellement, dans les 3 premières heures après injection, les nanoparticules vers les tumeurs surexprimant les intégrines αvβ3. Une biodistribution particulière des lipidots dans les organes stéroïdiens (surrénales, ovaires) a été observée avec une localisation spécifique dans les zones synthétisant les hormones stéroïdiennes (le corps jaune pour les ovaires, la zone corticale pour les surrénales). Cette affinité unique a été mise à projet pour cibler des tumeurs hormono-dépendantes, ainsi que pour encapsuler des hormones ovariennes pour le traitement hormonal substitutif ou le contrôle de la procréation. / Nanomedicine is a fast growing field since the development of liposomes, nanovectors able to encapsulate in their core or phospholipid bilayer hydrophilic or amphiphilic molecules for drug delivery purposes. Nowadays, most of the new synthetized therapeutic compounds are hydrophobic, necessitating the development of new types of nanocargos. Lipidots, 50 nm diameter biocompatible solid lipid nanoparticles, composed of a mixture of oil, wax and lecithin stabilized by a shell of pegylated surfactants, are used to encapsulate highly hydrophobic compounds in their core for vectorization purpose. Nuclear agents for simple photon emission tomography, or near infrared fluorescent dyes, have been encapsulated in the lipidot core, to assess the biodistribution of these nanoparticles in healthy mice as well as in a large range of tumor models. A targeting peptide, the cRGD motif, was also grafted on the surface of lipidots to vectorize preferentially the nanoparticles to tumors overexpressing αvβ3 integrins. An unexpected lipidot biodistribution in steroid organs (adrenal, ovary) was observed, with a specific localization in areas of steroid hormones synthesis (corpus luteum in ovaries, cortex for adrenals). This unique lipidot affinity was used to target hormono-dependent cancer cells, as well as to encapsulate ovarian hormones, like estradiol or ethynil estradiol, for hormone substitution therapy or birth control.

Indocyanine green (ICG) is a fluorescent dye used as an indicator in medicine and surgery. The maximum absorption wavelength of ICG is at 785 nm, while the maximum emission is around 820 nm. ICG is nontoxic and is rapidly excreted into the bile. Near infrared (NIR) fluorescence imaging or spectroscopy offer new settings for seeing the blood vessels, and also in oncological applications for finding sentinel lymph nodes (SLN) to investigate if the cancer has spread from the tumor to the lymphatic system. Given the aforementioned applications, the aim of this thesis was to develop a hardware control and a user interface in LabVIEW, and to evaluate the software, as well as the instrumentation using phantom measurements.The system consisted of a spectrometer, a laser (785 ± 5 nm) for ICG excitation, optical filters, and a fiber optical probe containing five fibers for light excitation, and one for light collection. The basic LabVIEW program designed for the spectrometer was used, and additional features were added such as the recording functions, online measurements, opening of the recorded files, saving comments, and a loop was created for the laser control. Optical phantoms were prepared to model tissue for measurements using 20 % intralipid that gave μs = 298 mm−¹ at the excitation wavelength. Agar 1% w/v and ICG were added to the phantoms using different fluorophore concentrations of 2 μg/mL, 10 μg/mL, 20 μg/mL, 25 μg/mL, and 40 μg/mL. The objective was to perform controlled measurements of steady state ICG fluorescence, the dynamics of photobleaching at different concentrations, and to find the optimal ICG concentration for obtaining the maximum fluorescence intensity. The light to excite ICG fluorescence emission was provided by using a laser output power of 10.4 mW and 200 ms of integration time in the spectrometer for optimal measurements.Measurements using the different gel phantoms showed maximum fluorescence ICG concentration to be between 16 μg/mL and 20 μg/mL. Moreover, photobleaching measurements showed to be ICG concentration-dependent, where those concentrations higher than the optimal one incrementally photobleached with time after being exposed to light. Higher concentrations presented an incremental photobleaching where they first reached a maximum peak and then the intensity decayed with time. Additionally, laser reflection at 782 nm showed that the reflection increased with time ranging from 130% – 460% as the ICG photobleached to 50% of its initial value. Normalization of ICG by the laser reflection signal was investigated to compensate for the intensity variations due to the measurement parameters including the distance from the light source to the target, and the angle of inclination of the probe. The lowest ICG concentration detectable by the system was 0.05 μg/mL.In conclusion, a LabVIEW hardware control and user interface was developed for controlling the spectrometer and the laser. Several measurements were made using the different phantoms, where the optimal concentration of ICG was estimated. It was shown that ICG fluorescence intensity and photobleaching behavior were dependent on the concentration. The results gave suggestions for future experimental design. / NIRF

Tato diplomová práce se zabývá vytvořením modelu signálu impedančního měření srdce (ICG signál). Impedanční kardiografie podává informaci o změně srdečního objemu během srdečního cyklu. Modelování signálu předchází statistická analýza vzájemné pozice ICG signálu vzhledem k dalším mechanickým srdečním signálům. Konstrukce modelu vychází z reálných nasnímaných signálů. Konečný ICG model je začleněn do již existujícího modelu mechanických interakcí mezi srdcem a plícemi. Výsledkem je funkční model kardio-respiračních interakcí, který bude sloužit v dalších částech výzkumu laboratoře PRETA.

La nanomédecine est un secteur d'activité en plein essor depuis le développement des liposomes, nanovecteurs permettant d'encapsuler des molécules hydrosolubles ou amphiphiles pour la délivrance de médicament. Les nouveaux agents thérapeutiques synthétisés étant de plus en plus lipophiles, le développement de nouveaux vecteurs nanoparticulaires permettant leur transport constitue aujourd'hui un enjeu majeur. Les lipidots, nanoparticules lipidiques solides biocompatibles de 50 nm de diamètre, composées d'un mélange d'huile, de cire et de lécithine stabilisées par une couronne de surfactants pegylés, permettent de transporter des composés hautement hydrophobes en leur cœur. Des agents nucléaires pour la tomographie à émission monophotonique et des agents de fluorescence ont pu y être encapsulés pour l'évaluation de la biodistribution de ces nanoparticules chez la souris saine ainsi que dans différents modèles tumoraux. Un peptide de ciblage, le cRGD a également été greffé à la surface des lipidots afin d'adresser préférentiellement, dans les 3 premières heures après injection, les nanoparticules vers les tumeurs surexprimant les intégrines αvβ3. Une biodistribution particulière des lipidots dans les organes stéroïdiens (surrénales, ovaires) a été observée avec une localisation spécifique dans les zones synthétisant les hormones stéroïdiennes (le corps jaune pour les ovaires, la zone corticale pour les surrénales). Cette affinité unique a été mise à projet pour cibler des tumeurs hormono-dépendantes, ainsi que pour encapsuler des hormones ovariennes pour le traitement hormonal substitutif ou le contrôle de la procréation.

Frågan om ”normal” respektive ”patologisk” sorg har under en lång tid varit ett omdiskuterat ämne inom psykologin och psykiatrin. En grupp forskare har tagit fram kriterier på ett syndrom som fått benämningen ihållande sorg (”prolonged grief”). Studier har visat på att ihållande sorg är ett distinkt syndrom separat från depression, posttraumatisk stressyndrom och generaliserat ångestsyndrom. Ihållande sorg föreslås ingå som en diagnos i de kommande versionerna av de diagnostiska manualerna DSM och ICD. Syftet med denna studie var att översätta självskattningsinstrumentet Prolonged Grief Disorder (PG-13) till svenska, och undersöka dess reliabilitet och validitet genom bland annat en explorativ och konfirmatorisk faktoranalys. Studien genomfördes på ett annonsrekryterat heterogent sample (n=162 varav 90 % var kvinnor) vad gäller typ av dödsfall och relation till den avlidne. Respondenterna besvarade en webb- eller pappersenkät som bestod av 75 items. PG-13 bedöms ha en hög reliabilitet, god begrepps- och samtidig validitet samt en måttlig diskriminativ validitet.

Didelė dalis širdies susirgimų diagnostinių kriterijų gaunama registruojant ir analizuojant kardiosignalus, kurie atspindi tiek elektrinės širdies veiklos sutrikimus (EKG), tiek ir hemodinaminės bei mechaninės veiklos pokyčius, t.y. impedanskardiograma (IKG) ir seismokardiograma (SKG). Dar daugiau, efektyvus širdies susirgimų diagnostikos problemų sprendimas yra naujų kardiosignalų analizės technologijų kūrimas. Jau kelis dešimtmečius Furjė transformacija taikoma EKG dažnumų analizei, tuo tarpu kai IKG ir SKG dažnio charakteristikų vertinimui šis metodas nebuvo naudojamas. Darbo tikslas buvo pritaikyti Furjė analizę įvertinant bei palyginant tris sinchroniškai užregistruotus kardiosignalus, nes jie atspindi elektrinės širdies, hemodinaminės bei mechaninės širdies veiklos pokyčius geriau nei vienas EKG signalas. Kitas darbo tikslas buvo pritaikyti Furjė analizę įvertinant bei palyginant trijų sinchroniškai užregistruotų signalų - EKG, IKG ir SKG dažnio charakteristikas ir koherenciją bei klasifikuoti dvi grupes - "sveikas" ir "ligonis". Rezultatai rodo, kad koherencijos vertinimas ir spektrinė analizė gali būti naudinga gali būti naudingas širdies kraujagyslių bei plaučių sistemų ligų diagnostikai. / A big part of heart disease diagnostics criteria is collected by registration and analysis of cardio signals that reflect the disturbances of the electric heart activity – electrocardiogram (EСG), changes of hemodynamic - impedance cardiograms (IСG) and mechanic activity - seismocardiogram (SСG). ECG analysis is generally applying in clinic practice, but usually in visual way only. Due to the development of the technologies, the bigger amount of data could be stored and more exact analysis of information could be carried out. Therefore, a solution of problem of effective diagnostics of heart diseases is the creation of new technologies for analysis of cardio signals. Previously Fourier series were applied to frequency analysis of ECG, but this method was not applied for estimation of ICG and SCG frequency characteristics. In this thesis the frequency analysis method was applied to three cardio signals, because they reflect the electrical and mechanical work of the human heart better as entirely ECG signal. The main aim of this work was to adapt Fourier transformation to assessing and comparing some characteristics of hereinbefore signals, such as coherence and classify two searching groups - “healthy” and “sick”. Results showed that rating of coherence and spectral analysis could be useful for rightly analyzing and classifying the searching groups.

Idiopathic Epiretinal membrane is a proliferation of contractile cells on the surface of the retina that typically occurs after posterior vitreous detachment. Though many questions have been raised on the causes of this condition, a greater debate has been on the treatment of this pathology. The literature suggest the potential benefit in peeling ILM, due to its inherent proliferative characteristics, along with the ERM, during the surgery, however sufficient data has yet to been found. Due to the lack of consensus in treatment of iERM, this study set forth to provide some insight on the surgical outcomes of patients that undergo combined peeling as well attempting to contribute to a potential surgical protocol in treating iERM. This was a retrospective case series study looking at 140 eyes from 126 iERM patients that underwent ERM surgical treatment at Beth Israel Deaconess Medical Center between 1998 and 2015. Pre- and post- operative visual acuities, lens status (phakic, aphakic, pseudophakic), type (kenalog with or without ICG) and duration (0.5min, 1 min, 1.5 min) of the stains used in the procedure, and any prior or successive surgeries were recorded and analyzed. Overall, ERM surgeries demonstrated a significant (p<0.0001) improvement in visual acuity. Furthermore, the combined peel patients demonstrated a significantly (p<0.0467) greater mean change in logMAR score when compared to ERM-only peel procedures. In addition, the combined peel group showed a smaller rate of recurrence. Lastly, simultaneous cataract surgery and the use of ILM stains did not have an impact on the outcome of ERM surgery. The study found that combined (ERM and ILM) peeling along with simultaneous cataract surgery, if a cataract was present, along with the utilization of ILM stains is cost-effective, safe, and effective approach in treating iERM and decreasing its recurrence.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21449号 / 医博第4416号 / 新制||医||1032(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 松原 和夫, 教授 川上 浩司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Purpose: One relevant aspect for anastomotic leakage in colorectal surgery is blood perfusion of both ends of the anastomosis. The clinical evaluation of this issue is limited, but new methods like fluorescence angiography with indocyanine green or non-invasive and contactless hyperspectral imaging have evolved as objective parameters for perfusion evaluation. Methods: In this prospective, non-randomized, open-label and two-arm study, fluorescence angiography and hyperspectral imaging were compared in 32 consecutive patients with each other and with the clinical assessment by the surgeon. After preparation of the bowel and determination of the surgical resection line, the tissue was evaluated with hyperspectral imaging for 5 minutes before and after cutting the marginal artery and assessed by 6 hyperspectral pictures followed by fluorescence angiography with indocyanine green. Results: In 30 of 32 patients the image data could be evaluated and compared. Both methods provided a comparable borderline between well perfused and poorly perfused tissue (p = 0.704). In 15 cases, the surgical resection line was shifted to the central position due to the imaging. The border zone was sharper in fluorescence angiography and was best assessed 31sec after injection. With hyperspectral imaging, the border zone was visualized wider and with more differences between proximal and distal border. Conclusion: Hyperspectral imaging and fluorencence angiography provide similar results in determining the perfusion border. Both methods allow a good and safe visualization of the blood perfusion at the central resection margin to create a well-perfused anastomosis.:Abbildungsverzeichnis II Abkürzungsverzeichnis III 1. Einleitung 1 1.1 Anastomoseninsuffizienz 1 1.2 Hyperspektralbildgebung 2 Methodik und technische Daten 2 1.3 Fluoreszenzangiographie mit Indocyaningrün 4 Methodik und technische Daten 4 Anwendungsgebiet 6 1.4 Chirurgische Technik 6 1.5 Studiendesign und intraoperative Bildgebung 7 1.6 Bisherige Ergebnisse 10 2. Publikation 12 3. Zusammenfassung der Arbeit 21 4. Literaturverzeichnis IV 5. Darstellung des eigenen Beitrags VIII 6. Erklärung über die eigenständige Abfassung der Arbeit IX 7. Danksagung X

Electrical impedance of biological matter is known as electrical bio-impedance or simply as bio-impedance. Bio-impedance devices are of great value for monitoring the pathological and physiological status of biological tissues in clinical and home environments. The technological progress in instrumentation has significantly contributed to the progress that has been observed during the last past decades in impedance spectroscopy and electrical impedance cardiograph. Although bio-impedance is not a physiological parameter, the method enables tissue characterization and functional monitoring and can contribute to the monitoring of the health status of a person. In this paper an inexpensive portable multi frequency impedance cardiograph device based on impedance spectroscopy technique has been developed. By means of this system the basic thoracic impedance range and the heart-action-caused changes of impedance can be measured and the hemodynamic parameters of the heart function can be determined. This system has small size and low current consumption. The impedance cardiograph signals of the electrodes configuration by Sramek, Penney and Qu in this work was measured; compared and summarized. The differences of the measuring method, the schematic circuit diagram, the measurement results and area of application between impedance cardiograph and impedance spectroscopy were discussed and compared. The performance of this sensor-system was evaluated.